U.S. Pat. No. 4,128,558 granted on Dec. 5, 1978 to Price et al. describes various aminoalkyl furan derivatives including ranitidine. Example 32 of U.S. Pat. No. 4,128,658 in particular describes the preparation of Form 1 ranitidine hydrochloride by dissolving rantidine in industrial methylated spirit (a solvent made up largely of ethanol) containing hydrogen chloride gas, and crystallizing with the addition of ethyl acetate. This procedure is unsatisfactory because of the instability of Form 1 rantidine hydrochloride in the described solvent crystallization system which contains ethyl acetate and ethanol. In particular, the process is inadequate for large scale production.
U.S. Pat. Nos. 4,521,431 and 4,672,133 granted to Crookes on Jun. 4, 1985 and Jun. 9, 1987, respectively, describe a crystalline form of rantidine hydrochloride which is designated as Form 2 and which purportedly has more favorable filtration and drying characteristics than the Form 1 ranitidine hydrochloride obtained from the process using hydrogen chloride gas in industrial methylated spirit and ethyl acetate, as described in Example 32 of U.S. Pat. No. 4,128,558. The Form 2 ranitidine hydrochloride of Crookes may be prepared by treating a solution of ranitidine in a hydroxylic solvent, e.g., a lower alkanol, with hydrochloric acid followed by crystallization at elevated temperatures by adding further quantities of solvent. Alternatively, Form 2 ranitidine hydrochloride may be prepared from previously isolated Form 1 or Form 2 ranitidine hydrochloride by dissolving the salt, e.g., by warming in an organic solvent such as methanol or ethanol, followed by cooling to cause crystallization of the Form 2 salt, optionally accompanied by the addition of an anti-solvent or by the addition of Form 2 seeds to induce crystallization.
The differences between Form 2 as described in U.S. Pat. Nos. 4,521,431 and 4,672,133 and Form 1 which is the product of Example 32 of U.S. Pat. No. 4,128,658 are characterized by infra-red spectra and x-ray powder diffraction patterns.
U.S. Pat. No. 5,338,871 to Ngooi et al. is directed to the preparation of pure Form 1 ranitidine hydrochloride by forming a solution of ranitidine hydrochloride in a solvent mixture comprising at least one lower aliphatic alcohol, preferably ethanol, and an aromatic hydrocarbon, preferably toluene, and initiating crystallization by seeding with crystals of pure Form 1 ranitidine hydrochloride.
Ranitidine hydrochloride Forms 1 and 2 both have histamine H.sub.2 -blocking activity. However, because of the progressing difficulties experienced with Form 1, e.g., its sensitivity to moisture and the inability to produce it in commercial quantities, Form 2 has been produced exclusively and used as the active ingredient in the treatment of conditions where there is hypersecretion of gastric acid, such as gastric and peptic ulceration, and in the treatment of allergic conditions where histamine is a known mediator. Form 2 is also used in the treatment of allergic and inflammatory conditions.
So that Form 1 may also be used to treat these conditions, there is a need for a process that will consistently produce pure and stable Form 1 ranitidine hydrochloride without any coproduction of, or conversion to, Form 2.